In allogeneic stem cell transplantation (SCT), donor T cells mediate beneficial immunity such as the graft-versus-leukemia (GVL) and graft-versus-tumor (GVT) effect and prevent graft rejection. However, donor T cells also initiate lethal GVHD. In murine studies, we have shown that CD4+ Th2 cells reduce GVHD. We have also shown that donor CD8+ Tc2 cells can mediate GVL and GVT effects and prevent marrow rejection with greatly reduced GVHD. As a translation of these results, we have initiated a clinical trial evaluating in vitro generated donor Th2 cells in the allogeneic SCT setting. Clinical trials evaluating Tc2 cells are also planned for the purpose of preventing graft rejection (in the setting of mismatched transplantation) and in the setting of tumor relapse post-transplant. Ongoing murine studies are evaluating the molecular mechanisms of Th2 and Tc2-mediated immunity in the transplant setting. Our lab is additionally evaluating T cell subsets, in particular the Th1 and Tc1 subsets, in the syngeneic setting. These subsets are associated with GVHD in the allogeneic setting, but are likely important anti-tumor mediators in the syngeneic setting. Murine studies are ongoing to evaluate the role of Th1 and Tc1 cells in anti-tumor immunity, particularly in the vaccine setting.